title: Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis.
abstract: OBJECTIVE
  To determine whether anticitrullinated protein antibodies (ACPA) exhibit specific changes in Fc glycosylation prior to the onset of arthritis.
  
  
  METHODS
  Serum samples of patients with ACPA-positive arthralgia (n=183) were collected at baseline and at various time points of follow-up. 105 patients developed arthritis after a median of 12 months (IQR 6-24) and were classified as having either rheumatoid arthritis (RA, n=48) or undifferentiated arthritis (UA, n=57) based on the 1987 American College of Rheumatology (ACR) criteria. ACPA and total serum IgG were isolated by affinity purification and cleaved by trypsin. ACPA-IgG1 Fc-glycopeptides were subsequently analysed by nano-liquid chromatography mass spectrometry and compared to those of total IgG1.
  
  
  RESULTS
  At baseline, ACPA-IgG1 and total IgG1 from arthralgia patients displayed similar Fc glycosylation patterns. By contrast, at the onset of arthritis, ACPA exhibited a decrease in galactose residues in RA patients, but not in UA patients. This decrease occurred around 3 months prior to diagnosis and was paralleled by an increase in systemic inflammation (erythrocyte sedimentation rate). Galactosylation of total IgG1 was also decreased in RA, but this did not precede the onset of arthritis. Interestingly, we additionally noted a higher degree of ACPA-IgG1 Fc core fucosylation at baseline as compared with total IgG1, which further increased prior to diagnosis.
  
  
  CONCLUSIONS
  ACPA display significant changes in Fc galactosylation and fucosylation prior to the onset of RA. These changes towards a more pro-inflammatory phenotype could be involved in driving the disease process.
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Rombouts
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Ewoud
authors.initials: E
authors.lastname: Ewing
authors.affiliation: Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands.
authors.forename: Lotte A
authors.initials: LA
authors.lastname: van de Stadt
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Maurice H J
authors.initials: MH
authors.lastname: Selman
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: André M
authors.initials: AM
authors.lastname: Deelder
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wuhrer
authors.affiliation: Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Dirkjan
authors.initials: D
authors.lastname: van Schaardenburg
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Hans U
authors.initials: HU
authors.lastname: Scherer
mesh_terms: D000328:Adult; D001168:Arthritis / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D005643:Fucose / Q000378:metabolism; D005690:Galactose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism*; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D010641:Phenotype; D011134:Polysaccharides / Q000378:metabolism*; D062706:Prodromal Symptoms
chemical_list: D001323:Autoantibodies; D007141:Immunoglobulin Fc Fragments; D010456:Peptides, Cyclic; D011134:Polysaccharides; C487763:cyclic citrullinated peptide; D005643:Fucose; D005690:Galactose
keywords: Ant-CCP; Autoantibodies; Inflammation; Rheumatoid Arthritis